The invention relates to novel vinylogous acid derivatives of formula I, a process and an intermediate for the manufacture of such compounds, pharmaceutical compositions containing such compounds, and the use of such compounds. The compounds of formula I are useful as Chymase inhibitors.
Chymase is a serine proteinase with an expression pattern strictly limited to a sub-population of mast cells (MCT mast cell). Chymase is activated only upon mast cell activation and degranulation which restricts the enzyme activity to MCT positive tissues. Chymase is specifically cleaving a number of pathologically relevant substrates (Raymond, W. W., S. W. Ruggles, et al.; JBC 2003 278(36): 34517-34524) whereby it can activate Angiotensin II, Endothelin, TGFb, Il1, SCF, collagenase and degrade proteins like Thrombin, FN, APO A1,2. This pattern renders chymase an attractive target for allergic, inflammatory and fibrotic diseases. Indeed a number of successful animal studies with chymase inhibitors have demonstrated efficacy in atopic animals, vascular injury and atherosclerosis (Doggrell S A, Wanstall J C Can J Physiol Pharmacol. 2005 February; 83(2):123-30; Lindstedt K A, Kovanen P T. Curr Opin Lipidol. 2004 October; 15(5):567-73; Reed C E, Kita H. J Allergy Clin Immunol. 2004 November; 114(5):997-1008; Takai S, et al, Eur J. Pharmacol. 2004 Oct. 6; 501(1-3):1-8; Takai S, et al, Trends Pharmacol Sci. 2004 October; 25(10):518-22; Takai S, Miyazaki M. Curr Vasc Pharmacol. 2003 June; 1(2):217-24).
Thus inhibition of chymase appears a useful modality in Allergy, Asthma, peripheral arterial occlusive disease, critical limb ischemia, vulnerable atherosclerotic plaque patients, unstable angina, congestive heart failure, left ventricular hypertrophy, ischemia reperfusion injury, cardiomyopathy, restenosis, rheumatoid arthritis, diabetic nephropathy, irritable Bowel Disease, Crones disease, wound healing (burns/ulcers in Diabetes/CLI).